North American hospitals are experiencing an epidemic of Staphylococcus aureus. This organism causes a wide range of diseases from minor skin infections to life-threatening sepsis, endocarditis, and pneumonia [2]. S. aureus is endowed with a wide range of virulence factors that enable its many disease manifestations. One of the defining characteristics of S. aureus that distinguishes it from less pathogenic species of staphylococci is its ability to clot anticoagulated blood [48,75]. This characteristic is due to two proteins, coagulase (Coa) and von Willebrand factor binding protein (vWbp). Coa and vWbp bind to and induce a conformational change in host prothrombin, which mimics the transition from the zymogen to activated thrombin, enabling the complex to cleave fibrinogen to fibrin [66,67,71,72,133,146,188]. Fibrin forms the mesh network of a blood clot.
Coa and vWbp play an important role during the pathogenesis of S. aureus infection [212]. Infection with double mutants in coa and vwb results in delayed mortality in a murine sepsis model and nearly eliminates the ability of staphylococci to form abscesses (Cheng et al 2010). A humoral immune response against Coa and vWbp provides protection against staphylococcal infection (Cheng et al 2010). Pharmacologic inhibition of the coagulases with direct thrombin inhibitors neutralizes the activity of Coa and vWbp and provides prophylactic protection against staphylococcal sepsis [20,177,213].
S. aureus can survive on dry surfaces, increasing the chance of transmission. Any S. aureus infection can cause the staphylococcal scalded skin syndrome, a cutaneous reaction to exotoxin absorbed into the bloodstream. S. aureus can also cause a type of septicemia called pyaemia that can be life-threatening. Methicillin-resistant Staphylococcus aureus (MRSA) has become a major cause of hospital-acquired infections.
S. aureus infections are typically treated with antibiotics, with penicillin being the drug of choice, but vancomycin being used for methicillin resistant isolates. The percentage of staphylococcal strains exhibiting wide-spectrum resistance to antibiotics has increased, posing a threat to effective antimicrobial therapy. In addition, the recent appearance of vancomycin-resistant S. aureus strain has aroused fear that MRSA strains for which no effective therapy is available are starting to emerge and spread.
An alternative approach to antibiotics in the treatment of staphylococcal infections has been the use of antibodies against staphylococcal antigens in passive immunotherapy. Examples of this passive immunotherapy involves administration of polyclonal antisera (WO00/15238, WO00/12132) as well as treatment with monoclonal antibodies against lipoteichoic acid (WO98/57994).
The first generation of vaccines targeted against S. aureus or against the exoproteins it produces have met with limited success (Lee, 1996) and there remains a need to develop additional therapeutic compositions for treatment of staphylococcus infections.